B187
Reversal of Bortezomib Resistance by a MCL-1/A1 targeting Small Molecule BH3 Mimetic in Mesothelioma
Alex Chacko1, Dario Barbone2, Nyree Crawford1, Luciano Mutti3, Patrick Johnston3, Giovanni Gaudino4, Dean Fennell1
1Queen’s University Belfast, Northern Ireland, UK, 2Lung Biology Centre, UCSF, San Francisco, USA, 3Lab. di Oncologia Clinica, Borgosesia, Italy, 4University of Piemonte Orientale, Novara, Italy
Background
Malignant Mesothelioma (MM) is an apoptosis resistant cancer. 20S-proteasome inhibition by Bortezomib (Bz) is an approved anti-cancer strategy under evaluation in MM based on preclinical data [1], and modulates the BCL-2 family [2].
Method and results
We explored Bz pharmacodynamics in MM, to better understand potential sensitivity/resistance mechanisms relevant to our Phase-II trial. Bz was a logfold more potent in REN compared with MPP89 cells. NOXA was upregulated in REN cells but not MPP89s. Isolated mitochondria from Bz primed MM cells were sensitized to exogenous BID-BH3 domain reflecting modulation of mitochondrial apoptosis signalling. Accordingly Bz caused mitochondrial cytochrome C release, BAK activation and depolarization. In MPP89 cells, Bz downregulated mitochondrial BCL-2/A1. BIM was upregulated and translocated to mitochondria binding, MCL-1 and de-repressing BAK. In MPP89 and REN spheroids, NOXA was not upregulated post Bz. In contrast, REN cells upregulated NOXA, which translocated to mitochondria and disrupted a high molecular weight MCL-1-BAK complex. NOXA RNAi protected against Bz and exogenous NOXA –BH3 (or obatoclax) induced apoptosis. Furthermore, obatoclax combined with bortezomib exhibited potent synergy in MPP89 cells.
Conclusion
NOXA facilitates Bz toxicity by modulating BCL-2 proteins. This model suggests that loss of critical components of this pathway may underlie therapeutic Bz resistance in MM, but may be overcome by inhibiting MCL-1/A1.
References
[1] Sartore-Bianchi et al., Clin Cancer Res 13, 5942
[2] Fennell et al, Oncogene 2008
